Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3W2UQS)

• DOT Name: Tumor necrosis factor receptor superfamily member EDAR (EDAR)
• Synonyms: Anhidrotic ectodysplasin receptor 1; Downless homolog; EDA-A1 receptor; Ectodermal dysplasia receptor; Ectodysplasin-A receptor
• Gene Name: EDAR
• Related Disease:
  Ectodermal dysplasia 10B, hypohidrotic/hair/tooth type, autosomal recessive
  Alzheimer disease
  Amyloidosis
  Breast cancer
  Breast carcinoma
  Dementia
  Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant
  Lung adenocarcinoma
  Melanoma
  Neoplasm
  Ectodermal dysplasia
  Autosomal dominant hypohidrotic ectodermal dysplasia
  Autosomal recessive hypohidrotic ectodermal dysplasia
  Androgenetic alopecia
  Baldness, male pattern
• UniProt ID: EDAR_HUMAN
• PDB ID: 7X9G
• Sequence:
  MAHVGDCTQTPWLPVLVVSLMCSARAEYSNCGENEYYNQTTGLCQECPPCGPGEEPYLSC
  GYGTKDEDYGCVPCPAEKFSKGGYQICRRHKDCEGFFRATVLTPGDMENDAECGPCLPGY
  YMLENRPRNIYGMVCYSCLLAPPNTKECVGATSGASANFPGTSGSSTLSPFQHAHKELSG
  QGHLATALIIAMSTIFIMAIAIVLIIMFYILKTKPSAPACCTSHPGKSVEAQVSKDEEKK
  EAPDNVVMFSEKDEFEKLTATPAKPTKSENDASSENEQLLSRSVDSDEEPAPDKQGSPEL
  CLLSLVHLAREKSATSNKSAGIQSRRKKILDVYANVCGVVEGLSPTELPFDCLEKTSRML
  SSTYNSEKAVVKTWRHLAESFGLKRDEIGGMTDGMQLFDRISTAGYSIPELLTKLVQIER
  LDAVESLCADILEWAGVVPPASQPHAAS
• Function: Receptor for EDA isoform A1, but not for EDA isoform A2. Mediates the activation of NF-kappa-B and JNK. May promote caspase-independent cell death.
• Tissue Specificity: Detected in fetal kidney, lung, skin and cultured neonatal epidermal keratinocytes. Not detected in lymphoblast and fibroblast cell lines.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  NF-kappa B sig.ling pathway (hsa04064)
• Reactome Pathway: TNFs bind their physiological receptors (R-HSA-5669034)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ectodermal dysplasia 10B, hypohidrotic/hair/tooth type, autosomal recessive	DISX74O5	Definitive	Autosomal recessive	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Amyloidosis	DISHTAI2	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Dementia	DISXL1WY	Strong	Genetic Variation	[4]
Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant	DISQEKEI	Strong	Autosomal dominant	[1]
Lung adenocarcinoma	DISD51WR	Strong	Genetic Variation	[5]
Melanoma	DIS1RRCY	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Altered Expression	[6]
Ectodermal dysplasia	DISLRS4M	moderate	Genetic Variation	[7]
Autosomal dominant hypohidrotic ectodermal dysplasia	DISGWW7F	Supportive	Autosomal dominant	[8]
Autosomal recessive hypohidrotic ectodermal dysplasia	DISGAO5V	Supportive	Autosomal recessive	[8]
Androgenetic alopecia	DISSJR1P	Limited	Genetic Variation	[9]
Baldness, male pattern	DIS9C9RO	Limited	Genetic Variation	[9]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Tumor necrosis factor receptor superfamily member EDAR (EDAR).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Tumor necrosis factor receptor superfamily member EDAR (EDAR).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Tumor necrosis factor receptor superfamily member EDAR (EDAR).	[14]

2 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Tumor necrosis factor receptor superfamily member EDAR (EDAR).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Tumor necrosis factor receptor superfamily member EDAR (EDAR).	[13]

References

• [1] Mutations in the human homologue of mouse dl cause autosomal recessive and dominant hypohidrotic ectodermal dysplasia. Nat Genet. 1999 Aug;22(4):366-9. doi: 10.1038/11937.
• [2] Genetic Risk as a Marker of Amyloid- and Tau Burden in Cerebrospinal Fluid.J Alzheimers Dis. 2017;55(4):1417-1427. doi: 10.3233/JAD-160707.
• [3] X-linked ectodermal dysplasia receptor is downregulated in breast cancer via promoter methylation.Clin Cancer Res. 2010 Feb 15;16(4):1140-8. doi: 10.1158/1078-0432.CCR-09-2463. Epub 2010 Feb 9.
• [4] Relation of Odor Identification with Alzheimer's Disease Markers in Cerebrospinal Fluid and Cognition.J Alzheimers Dis. 2017;60(3):1025-1034. doi: 10.3233/JAD-170564.
• [5] Geographic Variation in EGFR Mutation Frequency inLung Adenocarcinoma May Be Explained by Interethnic Genetic Variation.J Thorac Oncol. 2018 Mar;13(3):454-458. doi: 10.1016/j.jtho.2017.11.128. Epub 2017 Dec 13.
• [6] The Ectodysplasin receptor EDAR acts as a tumor suppressor in melanoma by conditionally inducing cell death.Cell Death Differ. 2019 Mar;26(3):443-454. doi: 10.1038/s41418-018-0128-1. Epub 2018 May 31.
• [7] The transcription factor NKX2-3 mediates p21 expression and ectodysplasin-A signaling in the enamel knot for cusp formation in tooth development.J Biol Chem. 2018 Sep 21;293(38):14572-14584. doi: 10.1074/jbc.RA118.003373. Epub 2018 Aug 8.
• [8] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [9] Detection and interpretation of shared genetic influences on 42 human traits.Nat Genet. 2016 Jul;48(7):709-17. doi: 10.1038/ng.3570. Epub 2016 May 16.
• [10] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [11] Quercetin induced cell apoptosis and altered gene expression in AGS human gastric cancer cells. Environ Toxicol. 2018 Nov;33(11):1168-1181. doi: 10.1002/tox.22623. Epub 2018 Aug 27.
• [12] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [13] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [14] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.